EDITORIAL

Myocardial stunning by gated SPECT: An old tool reinvented in a stunning turn

Wael A. AlJaroudi, MD, FASNC,a and Fadi G. Hage, MD, FASNCb,c

a Division of Cardiovascular , Clemenceau Medical Center, Beirut, Lebanon b Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL c Section of Cardiology, Birmingham Veterans Affairs Medical Center, Birmingham, AL

Received Nov 3, 2017; accepted Nov 3, 2017 doi:10.1007/s12350-017-1127-1

the ischemic burden.3 However, it is important to point See related article, pp. 833–840 out that factors other than myocardial ischemia, such as hemodynamics and myocardial innervation, play a key role in the lack of augmentation of LVEF with Stunning: to deprive of strength; to astonish; to vasodilator stress.5,6 shock or overwhelm; to daze or bewilder. Stress-induced new wall motion abnormality is Dictionary.com highly specific for CAD and ischemia with imaging modalities that focus on myocardial motion such as Left ventricular (LV) myocardial stunning is a and cardiac magnetic resonance phenomenon described decades ago as a transient acute imaging.7 With gated Tc-99m single-photon emission systolic dysfunction secondary to myocardial ischemia.1 computed tomography (SPECT), reversible regional The pathogenesis of myocardial stunning involves dis- wall motion abnormalities with exercise have a speci- ruption of calcium homeostasis and oxygen-free radical ficity of 100% to detect significant CAD ([ 70% injury.2 In patients with normal myocardial perfusion, epicardial stenosis of a coronary artery on angiogram), LV myocardial contractility increases during stress with good correlation with coronary artery jeopardy testing, whether exercise or pharmacologic, with corre- score (R = 0.49, P \ 0.0001), although with limited spondent increase in LV (EF).3–6 This sensitivity (53%).8 After adjusting for Duke Treadmill is most evident during stress echocardiography where Score and other covariates, reversible wall motion live stress imaging shows augmented contractility of abnormality on stress gated SPECT remains an inde- myocardial segments. In patients with significant coro- pendent predictor of severe CAD. Similarly, worsening nary artery disease (CAD), supply demand mismatch of LVEF with vasodilator 201-Thallium-gated SPECT during stress testing results in myocardial perfusion has a high specificity for significant CAD, albeit with abnormality followed by abnormal segment contractil- low sensitivity.9 ity, an energy-dependent phenomenon, causing transient In addition to global LVEF, assessment of regional stunning of the myocytes.7 While this is more common wall motion is also feasible with gated SPECT with exercise or dobutamine, vasodilator stress testing myocardial perfusion imaging (MPI) although quantifi- can also induce myocardial ischemia (steal-phe- cation and scoring are not routinely performed and nomenon). If the ischemic burden is significant, global reported. The visual assessment of segment thickening is LVEF may decrease at peak stress in up to half of subjective and sometimes limited by the tracer count, patients. The best predictor of this post-stress stunning is frame rate, and attenuation artifact. Another tool pro- vided by gates images is mechanical synchrony using phase analysis. This valuable tool is automated, repro- ducible, repeatable, and transcends the 8 to 16 frame rate Reprint requests: Fadi G. Hage, MD, FASNC, Division of Cardio- of the gated images though a complex Fourier trans- vascular Disease, Department of Medicine, University of Alabama formation giving it an apparent frame rate of 1/64th at Birmingham, 306 Lyons-Harrison Research Building, 701 19th 10 Street South, Birmingham, AL 35294-0007; [email protected] frames/cycle. Moreover, phase analysis provides J Nucl Cardiol 2019;26:841–4. regional synchrony and onset of mechanical contractility 1071-3581/$34.00 for each myocardial segment. During stress testing, the Copyright Ó 2017 American Society of Nuclear Cardiology.

841 842 AlJaroudi and Hage Journal of Nuclear CardiologyÒ Wall thickening and stunning May/June 2019 improvement in systolic function and contractility ischemia and time of acquisition, and the correlation reserve translates into improvement in mechanical syn- between ischemic burden and LV stunning was strongest chrony and narrower phase SD and histogram with early imaging (i.e., stress 1). Therefore, the authors bandwidth.4 The effect of ischemic burden on mechan- concluded that ‘‘early post-exercise imaging is feasible, ical synchrony is controversial. In a small study, the and can potentially improve the detection of post-is- presence of reversible perfusion defect did not alter the chemic stunning without compromising image quality indices of mechanical dyssynchrony by phase analysis and perfusion data’’.18 In another recent study, Brodov from gated SPECT; however, there was no angiographic et al 19 performed serial 2-minutes acquisitions post- data to correlate with anatomic stenosis.11 In a more regadenoson injection with a high-efficiency solid-state recent study, patients with multi-vessel CAD confirmed CZT SPECT camera in 50 patients. They showed that with had significantly more global and myocardial stunning (i.e., negative LVEF reserve) was territorial dyssynchrony at early post-stress than at rest detectable in patients with myocardial ischemia only in 201-Thallium SPECT MPI.12 Another study measured early acquisitions (images obtained at the 5th and 9th LV synchrony immediately after reperfusion therapy minutes). Importantly, later acquisitions did not show using real-time three-dimensional echocardiography and significant correlation between myocardial ischemia and showed strong correlation with 201-Thallium and 123I- LVEF reserve. These studies are in line with the robust beta methyl-iodophenyl pentadecanoic acid mismatch data demonstrating the prognostic value of LVEF with dual isotope SPECT, a reflection of acute reserve with PET imaging which occurs early after peak myocardial stunning.13 In patients with ischemic car- stress.5,6,20,21 diomyopathy, independent predictors of worsening LV In the current paper, Bestetti et al 22 evaluated the mechanical dyssynchrony at peak stress were perfusion additional value of systolic wall thickening from gated defect size, resting rate, lower LVEF, and lack of SPECT images in diagnosing LV myocardial stunning in contractility reserve.14 Furthermore, worsening of patients with known significant CAD. Among 2064 mechanical dyssynchrony was an independent predictor patients who underwent 2 days exercise stress/rest 99m- of all-cause mortality (HR 1.19 [1.01;1.38], per 10° Tc SPECT MPI (images obtained 45 to 60 minutes after increase in phase SD, P = .04) and reclassified 18% of tracer injection), 91 patients were selected for final patients with IDI 1.4% (P = .02) and net reclassification analysis who had: 1) reversible perfusion defect with index of 9% (P = .057).14 summed difference score (SDS) C 5 and 2) severe CAD Although most studies examining stunning focused (C 70% epicardial stenosis) on a coronary angiogram on impaired systolic function and contractility, the performed within 3 months of the MPI. Wall thickening diastolic function which is also an energy-dependent (WT) was graded on a four-point scale (0 = normal, process, is affected prior to systolic function. In a recent 1 = mildly impaired, 2 = moderately impaired, study, worsening of diastolic function and a change in E/ 3 = severely impaired to absent thickening) based on e0 [ 25% (stress-rest) increased the likelihood of a the visual assessment of myocardial wall brightening positive stress echocardiogram, and of obstructive CAD from to using the 20 segment model. by angiography.15 Similarly, diastolic dyssynchrony was WT-SDS was defined as the difference in WT score shown to be associated with peri-infarct stunned myo- between stress and rest. cardium that is salvaged with primary intervention.16 In this cohort with CAD by angiography and For both systolic and diastolic function assessments ischemic burden on MPI (mean SDS 8.19 ± 2.9), the with gated MPI, the key parameter is early imaging. post-stress LVEF was significantly lower than rest While the perfusion images with MPI reflect myocardial LVEF (48.1% ± 10.3% vs. 50.3% ± 10.7%; perfusion at peak stress (time of tracer injection), seg- P = 0.0001), and there was significant segmental wall ment contractility is a reflection of myocardium at time motion dysfunction with mean WT-SDS 4.44 ± 4.13. of imaging which is routinely delayed from peak stress LV stunning, defined as drop in LVEF (stress-rest) by by 15 to 60 minutes depending on type of stress test and C 5%, was detectable in 28% of patients. The study tracer.17 Stunning is a time-dependent phenomenon that demonstrated an inverse linear correlation between WT- may have resolved by the time-gated images are SDS and DLVEF (RHO =-0.33, P = 0.002). Based obtained. In a recent multicenter study from the Inter- on the regression equation, a threshold of 11.8 for WT- national Atomic Energy Agency, 229 patients SDS has to be present before a significant drop (C 5%) underwent exercise stress SPECT MPI. Stress images in LVEF is observed. Furthermore, when the population were acquired 15 ± 5 minutes after radiotracer injection was divided into those with mild (SDS \ 8) and severe (Stress-1) and repeated at 60 ± 15 minutes (Stress-2), ischemia (SDS C 8), WT-SDS was significantly higher while rest images were acquired 60 minutes post injec- in those with severe ischemia (5.67 ± 4.11 vs tion. The stress LVEF was associated with the degree of 3.18 ± 3.8; P = 0.003) while DLVEF was not different Journal of Nuclear CardiologyÒ AlJaroudi and Hage 843 Volume 26, Number 3;841–4 Wall thickening and stunning between the two groups. The authors concluded that information in patients with normal perfusion pattern, WT-SDS quantifies the stunning phenomenon and is an but these patients were excluded from this study by independent parameter with the strongest correlation design. Lastly, we need to explore whether WT-SDS with SDS and reversible systolic dysfunction (DLVEF), adds incremental information to other non-perfusion and hence, should be routinely evaluated and reported. variables such as transient ischemic dilation,24,25 ST- While the study underscores an important tool to segment shift,26,27 heart rate response,28–30 myocardial assess the stunning phenomenon that is readily available blood flow reserve,31–33 LV dyssynchrony,14,34,35 and on gated images but seemingly cast away and ignored, other non-perfusion variables.23 there are several key issues to consider. First, WT is In conclusion, the study by Bestetti et al 22 rein- visually assessed and hence affected by readers’ exper- troduced a long forgotten parameter, WT-SDS, and tise; the interobserver and intraobserver variability of demonstrated that it correlates better with ischemic the WT-SDS score are not reported. Second, areas of burden than LVEF reserve and therefore may improve infarct can be tethered by adjacent normal segment the detection of myocardial stunning. Larger studies are contractility, leading to false labeling a segment as needed to validate this score, measure its interobserver having normal contractility and reducing WT-SDS and intraobserver variability, assess whether regional score. Third, the WT-SDS score is a global score that WT-SDS is better than global score, apply it in cohorts does not reflect regional systolic dysfunction; therefore, with normal and abnormal myocardial perfusion, and WT-SDS will be unchanged if a segment becomes aki- evaluate whether it adds diagnostic and prognostic value netic, while WT in other segments improves during beyond LVEF, mechanical dyssynchrony, TID, and stress. Fourth, the temporal resolution of the gated other non-perfusion variables. Indeed, we may find out images with 8 frames/cycle is a limiting effect. Fifth, the that the information provided may be stunning. value of WT-SDS in vasodilator stress testing needs to be established since this study included only patients Disclosure undergoing exercise stress. Sixth, the effect of timing of gated image acquisition as discussed above needs to be Dr. Hage has received research Grants from Astellas established. Last, a 20 segment model was used in this Pharma USA study rather than the conventional 17 segment model. How to define myocardial stunning poses several challenges. If stunning is defined as a drop in LVEF References (stress-rest) by 5%, only a quarter of patients with myocardial ischemia in this study had stunning, with the 1. Opie LH. The ever expanding spectrum of ischemic left ventric- majority of patients (62/91) having no change in LVEF ular dysfunction. Cardiovasc Drugs Ther 1994;8:297-304. (DLVEF between – 5% and ? 5%). While the authors 2. Bolli R, Marban E. 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